Elevated norepinephrine metabolism is linked to cortical thickness in the context of Alzheimer's disease pathology.

Affiliation

van Hooren RWE(1), Verhey FRJ(2), Ramakers IHGB(2), Jansen WJ(2), Jacobs HIL(3).
Author information:
(1)Faculty of Health, Medicine and Life Sciences; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands. Electronic address: [Email]
(2)Faculty of Health, Medicine and Life Sciences; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.
(3)Faculty of Health, Medicine and Life Sciences; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands; Faculty of Psychology and Neuroscience, Department of Cognitive Neuroscience, Maastricht University, Maastricht, The Netherlands; Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. Electronic address: [Email]

Abstract

Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Aβ42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of Aβ42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes.